Functional analyzes for common receptor tyrosine kinases of hematopoietic stem cells and vascular endothelial cells

造血干细胞和血管内皮细胞共同受体酪氨酸激酶的功能分析

基本信息

批准号：
08457279
负责人：
SUDA Toshio
金额：
$ 4.74万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457279/
关键词：
AGM region Hemangioblast Angiopoietin TEK 血液幹細胞血管内皮細胞 TIE アンギオポエチレン

项目摘要

Association between hematopoietic stem cells and their microenvironment are central to the development and maintenance of a functional hematopoietic system. The TEK receptor tyrosine kinase and its ligands angiopoietin-1 and -2 have been documented to be involved in the formation of the embryonic vasculature. Although the defect of vasuculo-angiogenesis was confirmed in both knockout mice of TEK and angiopoietin-1, the precise function of these molecules has not been well understood. Here, we evaluated the expression and function of TEK during embryogenesis, especially in the AGM (aorta-gonad-mesonephros) region, omphalo-mesenteric artery and vitelline artery, where definitive hematopoiesis newly takes place. In the vitelline artery at E9.5, TEK^+ hematopoietic cells aggregated each other and adhered to TEK^+ endothelial cells. Definitive hematopoiesis was not detected in TEK-deficient embryo. Soluble TEK protein inhibited the development of hematopoiesis and angiogenesis in AGM explant culture, and TEK knockout mice showed severely impaired definitive hematopoiesis. In vitro study, we found a novel function of angiopoietin-1 and -2 which promote expressing TEK cells to adhere to fibronectin and to aggregate each other. Finally, we showed that supplement of VEGF in the presence of angiopoietins promoted the proliferation of both hematopoietic cells and endothelial cells. These data provide a new regulatory system of the development and maintenance of definitive hematopoiesis through interaction with microenvironment.

造血干细胞与其微环境之间的关联对于功能性造血系统的发育和维持至关重要。 TEK 受体酪氨酸激酶及其配体血管生成素-1 和-2 已被证明参与胚胎脉管系统的形成。尽管在 TEK 和 angiopoietin-1 敲除小鼠中均证实了血管生成缺陷，但这些分子的确切功能尚未得到充分了解。在这里，我们评估了胚胎发生过程中 TEK 的表达和功能，特别是在 AGM（主动脉 - 性腺 - 中肾）区域、脐 - 肠系膜动脉和卵黄动脉，这是新发生确定性造血的地方。在E9.5的卵黄动脉中，TEK^+造血细胞彼此聚集并粘附到TEK^+内皮细胞。在 TEK 缺陷胚胎中未检测到确定的造血作用。可溶性 TEK 蛋白抑制 AGM 外植体培养物中造血和血管生成的发育，TEK 敲除小鼠显示出严重受损的最终造血功能。在体外研究中，我们发现了angiopoietin-1和-2的新功能，可以促进表达TEK细胞粘附纤连蛋白并相互聚集。最后，我们发现在血管生成素存在的情况下补充 VEGF 可以促进造血细胞和内皮细胞的增殖。这些数据提供了通过与微环境相互作用来发育和维持最终造血的新调节系统。